GENO- structural chromosomal abnormalities

Question 1

what are the types of structural abnormalities

Answer 1

translocations - reciprocal, robertsonian 
inversion
deletion
duplication
rings
isochromosomes

Question 2

what is meant by translocation structural abnormality

Answer 2

exchange of two segments between non-homologous chromosomes - between non-paired chromosomes

Question 3

how does tetravalence occur

Answer 3

during meiosis - chromosomes want to align with homologous pair- if there has been swapping of material they no longer math and cannot align so form a tetravalent / quadrivalent

Question 4

what happens when a tetravalent cell divides

Answer 4

when the cell divides it takes with them one half of the tetravalent structure - it will take a complete copy and a variant - when they are fertilised they will then end up with trisomy of part of the translocated part and monosomy of the other

Question 5

what happen if division occurs in a way in which the gamete contains both the translocated / complete chromosomes

Answer 5

the individual is a balanced carrier

Question 6

what are the consequences of reciprocal translocation

Answer 6

may lead to miscarriage
learning difficulties, physical disabilities
tend to be specific to each individual so exact risks and clinical features vary

Question 7

what is Robertsonian translocation

Answer 7

involves just the acrocentric chromosomes (p arms)

the p arms get lost and the q arms of the chromosome join together

Question 8

which are the acrocentric chromosomes

Answer 8

13,14,15,21,22,Y

Question 9

can you be ‘normal’ with 45 chromosomes

Answer 9

yes - Robertsonian translocation - you can still have all the relevant genetic material

Question 10

what do the p arms contain

Answer 10

RNA

Question 11

which Robertsonian translocations are relatively common

Answer 11

13: 14
14: 21
21: 21 - downs syndrome - 100% risk

Question 12

what is meant by NHEJ

Answer 12

non-homologous end joining

Question 13

what is the purpose of NHEJ

Answer 13

DNA repair mechanism
double stranded DNA breaks
rejoins the chunk of broken DNA

Question 14

what happens the NHEJ goes wrong

Answer 14

can join the broken chunk of DNA into another chromosome

creating derivative chromosomes

Question 15

are derivative chromosomes a problem

Answer 15

not usually in a healthy individual as they usually have one copy of the complete chromosome which makes up for the broken one - this person is known as a balance translocation carrier

it can be a problem though depending on what chromosomes are involved

Question 16

what is the Philadelphia chromosome

Answer 16

generated due to translocation between chr 9 and 22

chromosome 9 contains ABL which is a protooncogene - when its on chromosome 9 it is non-oncogenic

on chromosome 22 there is the BCR gene (prone to breaking)

translocation of ABL onto C22 creates a fusion gene which triggers oncogenic potential of ABL leading to leukaemia / myeloma

Question 17

what are features of the outcomes of translocations

Answer 17

very difficult to predict
only have approximate probability of producing possible gametes
some unbalanced translations may lead to spontaneous abortion - early conception
some may lead to miscarriage later in conception
some may result in live-born baby with various problems

Question 18

what is meant by terminal deletion

Answer 18

genes at the end of the telomere is lost

Question 19

what is meant by interstitial deletion

Answer 19

genes in the middle of the telomere are lost and the ends are joined together - the greater the deletion the easier it is to detect and diagnose

Question 20

explain what is meant by unequal crossing over

Answer 20

at myosis - alleles should align perfectly and then exchange genetic material (normal)
if they have misaligned you can get simultaneous deletions and duplications
end up with normal non-recombinants but also one copy with deletion and one with duplication
meaning an individual with this unequal crossing over will either be monosomic or have three copies

Question 21

what are sources of sample for genetic testing

Answer 21

prenatal - invasive - amniocentesis (amniotic fluid), chorionic villus samples (placenta), cell free foetal DNA

post natal - blood, saliva

Question 22

explain how structural abnormalities can be detected using stained metaphase chromosomes

Answer 22

most common
g banding - giemsa stain
can be seen under the microscope and detect large scale abnormalities
looks for aneuploidies, translocation and large deletions

Question 23

explain how structural abnormalities can be detected using FISH

Answer 23

fluorescent in situ hybridisation - specific to parts of the genome
looks for aneuploidies, translocations and large deletions
traditional FISH - need to know what youre looking for

cultured cells - metaphase spread
fluorescent probe

Question 24

what is spectral karyotyping

Answer 24

painting all the chromosomes so no need for a hypothesis of what is wrong before hand - compare what is different to what you expected

Question 25

explain how structural abnormalities can be detected using array CGH

Answer 25

array comparative genomic hybridisation
for detection of sub-microscopic chromosomal abnormalities
patient DNA labelled green
control DNA labelled red
complete process
measure of fluorescent signals compare control and patient DNA

looks for microdeletions and duplications

Question 26

explain how structural abnormalities can be detected using QF-PCR

Answer 26

interested in peaks - healthy individual = 2 same size peaks / single large peak
trisomy 2 peaks but one is twice size of other / 3 peaks

quick
looks for aneuploidies - have to know what youre looking for so know what microsatellites to target

Question 27

NIPT/ NGS

Answer 27

non-invasive prenatal testing / next generation sequencing

NIPT- cell free foetal DNA
maternal blood sample
trisomy testing

NGS- high chance indicator for an invasive test

Question 28

how do you detect microsatellites

Answer 28

isolate DNA from individual
design primers specific to flanking sequence
PCR amplification
gel electrophoresis
homozygotes - single product of a specific size
heterozygotes - two different sized products